PROJECT SUMMARY/ABSTRACT Traverse Biosciences Inc. is a pre-clinical stage drug development company working to commercialize new chemical entities which act to resolve inflammatory conditions through pleiotropic host-modulation of pathologically unrestrained matrix metalloproteinases (MMPs) and pro-inflammatory cytokines. The company's lead drug candidate, TRB-N0224, is a proprietary chemically modified curcumin developed by the co-inventor of Periostat and Oracea, currently the only FDA-approved MMP inhibitors. Periodontal disease is a chronic inflammatory condition involving interactions between oral bacterial products, numerous cell populations in the host tissues, and inflammatory mediators, such as cytokines, chemokines, arachidonic acid metabolites and proteolytic enzymes (including matrix metalloproteinases), which collectively contribute to tissue destruction and bone resorption. The Centers for Disease Control (CDC) estimates that the prevalence of periodontitis in U.S. adults aged 30 years and older is 47.2% (64.7M), and the prevalence of mild, moderate, and severe periodontitis is 8.7% (11.9M), 30.0% (41.1M), and 8.5% (11.7M), respectively. Periodontal disease has also been associated with other chronic conditions such as heart disease, diabetes, and various cancers. Most current drug therapies are primarily focused on the management of the microbial biofilm, not taking into account the central role of inflammation in causing tissue damage, which makes this therapy only partly effective. TRB-N0224 exhibits pleiotropic anti-inflammatory effects as a broad-spectrum MMP modulator, as well as an inhibitor of pro-inflammatory cytokines such as IL1-?, TNF-?, and IL-6, likely through interruption of the NF-kB pathway. TRB-N0224 acts to resolve inflammation via a multi-target, host-modulatory approach that overcomes the challenges of redundancy, compensation and necessity exhibited by the immune system Curcumin was chosen as a parent structure because it also has a 1,3-diketo moiety similar to that of the tetracyclines, and chemical modifications were pursued to overcome limited clinical use of curcumin due to its insolubility, rapid metabolism and modest biological activity. Our long-term goal is to develop an effective inhibitor of inducible MMPs with minimal side effects and toxicity that will significantly reduce the complications associated with periodontal disease. The objective here, which is the next step in the pursuit of our goal, is to test the efficacy of our lead compound, TRB-N0224, in a naturally-occurring canine model of periodontal disease. Our Phase II Hypothesis is that administration of TRB-N0224 will improve clinical assessments, including bleeding on probing and attachment loss, and protect alveolar bone from MMP damage in a naturally-occurring canine model of periodontal disease. We anticipate that TRB-N0224 will also lower the gingival tissue and serum levels of pro-inflammatory mediators. Our specific aims are to evaluate the effectiveness of our lead compound, TRB-N0224, to treat periodontal disease using a naturally-occurring canine model. Bone loss will be determined radiographically by measuring the distance from a fixed anatomical landmark, the cemento-enamel junction, to the alveolar bone crest, and levels/activity of MMPs and inflammatory cytokines will also be assessed. Successful completion of Phase II will allow us to pursue follow- on funding from private sources and/or a strategic partner to support pre-clinical testing of TRB-N0224 in preparation for a Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA). We hope to commercialize TRB-N0224 as an FDA-approved pharmaceutical intervention for the treatment of periodontal disease in an orally-administer (i.e. systemic) formulation, and intend to pursue pre-clinical and clinical development to demonstrate the safety and efficacy of this lead drug candidate.